The purpose of this application is to obtain basic information concerning vascular endothelial cell (EC) injury or perturbation and to determine the impact such an alteration has on the development of atherosclerosis. With this objective, we will pay particular attention to the role of low density lipoprotein (LDL) in causing EC perturbation. LDL is of special concern since it is a well-known risk factor,in high concentrations, for the development of atherosclerosis. The experiments proposed will use LDL concentrations associated with the premature development of atherosclerosis. The intent is to further develop an understanding of EC perturbation both in vivo and in vitro by extending prior studies in rabbits and in cell culture. The cause of in vivo EC dysfunction will be investigated by charting the development and delineating the mechanism of lipid-induced aortic hyperpermeable regions. Detailed parallel investigations will be carried out in cell culture by protracted EC exposure to LDL concentrations associated with the early development of atherosclerosis. Investigated, will be changes in membrane physiology, eicosanoid metabolism, and the generation of oxygen free radicals. Likely, each of these processes bears substantively on the induction of EC perturbation. We will also explore the implications of these findings on EC permeability, the generation of endothelial derived relaxation factor, and monocyte chemoattraction; all of consequence in vascular disease. The overall hypothesis to be investigated is that LDL induces subtle changes in the endothelium that contributes to the development of intimal disease and atherosclerosis. With these experiments, it is our intent to develop considerable new basic information to further fundamental understanding of the pathobiology of atherosclerosis.